Chimeric Antigen Receptor (CAR) T cell therapy for viral infectious diseases needs to target both the infected cell and the pathogen to break the replication cycle. We have recently conceptualized a technology termed Hybrid CAR, where the cell transduced to express anti-HIV chimeric receptor simultaneously secretes potent, broadly neutralizing antibodies capable of deactivating HIV and mediating Fc receptor functions. Here we propose to verify whether the secreted antibodies protect the Hybrid CAR T cell itself from being infected. Rendering classical CAR-T cells resistant to HIV is currently accomplished by shRNA or CRISPR-mediated impairment of viral coreceptor expression. However, to ensure complete protection both the CXCR4 and CCR5 silencing or knock-out are essential since the HIV virus has the ability to switch tropism. Moreover, lack of CXCR4 and/or CCR5 expression can have detrimental effects on T cell function. In our approach, locally secreted antibodies will prevent HIV from infecting the cell without the need for coreceptor manipulation. The second goal of the project is to evaluate whether different cytokine cocktails can improve the secretory function of Hybrid CAR T cells to boost antibody production for further enhancement of this technology.